1. health and fitness
2. disease

American Thoracic Societv
Idiopathic Pulmonary Fibrosis: Diagnosis and Treatment
International Consensus Statement
T HIS J OINT S TATEMENT
A DOPTED
BY THE
OF THE
ATS B OARD
A MERICAN T HORACIC S OCIETY (ATS),
OF
D IRECTORS , JULY 1999
AND BY THE
Many acute and chronic lung disorders with variable degrees
of pulmonary inflammation and fibrosis are collectively referred to as interstitial lung diseases (ILDs) or diffuse parenchymal lung diseases. Idiopathic pulmonary fibrosis (or cryptogenic fibrosing alveolitis) (IPF or CFA) is one of several
idiopathic interstitial pneumonias. IPF is now recognized as a
distinct clinical disorder. Despite major accomplishments in
our understanding of the pathogenesis of lung fibrosis (l), the
diagnosis and management of patients with IPF continues to
pose significant challenges (24).
AND THE
E UROPEAN R ESPIRATORY S OCIETY (ERS)
WAS
ERS E XECUTIVE C OMMITTEE , OCTOBER 1999
view of the data and writing of a specific section of the statement. The final statement was drafted after a series of meetings of the entire committee.
The level of evidence for the recommendations made in
this statement is largely that of expert opinion developed by
consensus. There is no supportive evidence from well conducted randomized controlled trials. The best evidence is from
well-conducted cohort studies or from case-control studies.
Even in these instances the diagnosis of IPF was frequently
not well established and the series often included patients with
other diseases or potential causes of lung fibrosis.
OBJECTIVE
This is an international consensus statement defining the diagnosis, evaluation, and management of patients with IPF that
has been produced as a collaborative effort from the American Thoracic Society (ATS), European Respiratory Society
(ERS), and the American College of Chest Physicians (ACCP).
The purpose of this consensus statement is to provide assistance to clinicians in the diagnosis and management of idiopathic pulmonary fibrosis (IPF). The targeted providers are
pulmonary subspecialists.
PARTICIPANTS
Panel members are experts in adult pulmonary diseases. Panel
members were nominated by the supporting associations. The
chair was selected by the American Thoracic Society. Panel
members were selected because of an interest and expertise in
the interstitial lung disease and to provide a range of opinions,
expertise, and geography.
EVIDENCE
The expert panel was provided with background articles that
reviewed the existing scientific evidence. Relevant articles from
the medical literature were identified by a MedLine search
(1966 to December 1998) of English language articles or articles with English abstracts, the bibliographies of the articles
retrieved, and the authors’ files. In addition, articles in other
languages were also obtained from the bibliographies of the
articles retrieved and were reviewed or translated by pulmonary physicians knowledgeable in this area. All articles in
which IPF was identified were included in this review. More
than 3,500 published reports were critically reviewed for information on IPF, including its physiologic, radiologic, and pathological findings; its pathogenesis, epidemiology, clinical presentation, and staging; its inheritance or familial occurrence;
its treatment (including lung transplant); and its prognosis.
The panel was divided into subgroups responsible for the reAm J Respir Crit Care Med Vol 161. pp 646-664,2000
Internet address: www.atsjournals.org
VALIDATION
The document was subjected to external review by peer reviewers identified by the American Thoracic Society, the American College of Chest Physicians, and the European Respiratory Society. It was submitted for review and approval to the
governing bodies of the American Thoracic Society, the European Respiratory Society, and the American College of Chest
Physicians.
OUTCOMES
The recommendations are applicable only to immunocompetent adult patients with IPF. The goals of this statement included reevaluating the roles of all investigative methods that
apply to diagnosing IPF. Therefore a revision of the definition
of IPF is provided in an effort to make it sufficiently sensitive
to include true positive cases while being sufficiently specific
to exclude those conditions most likely to be confused with
IPF. Key conclusions or recommendations from this consensus panel include the following:
1. The committee concludes that usual interstitial pneumonia (UIP) is the histopathological pattern that identifies patients with IPF. The histopathologic patterns of desquamative
interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RBILD), nonspecific interstitial
pneumonia (NSIP), lymphoid interstitial pneumonia (LIP),
acute interstitial pneumonia (AIP), and idiopathic bronchiolitis obliterans organizing pneumonia (idiopathic BOOP) are
considered separate entities and are to be excluded from the
group of patients with IPF.
2. Clinical criteria are specified for determining the presumptive diagnosis of IPF and distinguishing IPF from other
diffuse parenchymal lung diseases.
3. The committee concludes that surgical lung biopsy
(open thoracotomy or video-assisted thoracoscopy) is recommended in most patients, especially those with suspected IPF
who have clinical, physiological, or radiological features that
are not typical for IPF and who are without contraindications
to surgery. A major purpose of histological examination is to
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American Thoracic Society
UJP from other histological subsets of the idiopathic interstitial pneumonias that have a better response to
available treatment.
4. The committee concludes that no data exist that adequately document any of the current treatment approaches
improves survival or the quality of life for patients with JPF.
5. The committee suggests that therapy is not indicated for
all patients with JPF. If therapy is recommended to a patient,
the panel proposes that it should be started at the first identification of clinical or physiological evidence of impairment or
documentation of decline in lung function. Recommendations
are made regarding therapy for patients with JPF.
6. The committee recommends that a combination of clinical, radiographical, and physiological parameters be used to
assess the clinical course and response to treatment of IPF.
7. The committee recommends that lung transplantation
be considered for those patients who experience progressive
deterioration and who meet the established criteria for lung
transplantation.
8. The committee recommends that a multicenter, international consortium be established to determine the natural history and optimal treatment strategy for the management of
patients with JPF.
distinguish
DEFINITION
JPF is defined as a specific form of chronic fibrosing interstitial
pneumonia limited to the lung and associated with the histologic appearance of usual interstitial pneumonia (UJP) on surgical (thoracoscopic or open) lung biopsy. The etiology is unknown. The definite diagnosis of JPF in the presence of a
surgical biopsy showing UJP includes the following:
1. Exclusion of other known causes of interstitial lung disease such as drug toxicities, environmental exposures, and collagen vascular diseases
2. Abnormal pulmonary function studies that include evidence of restriction (reduced VC often with an increased
FEV,/FVC ratio) and/or impaired gas exchange [increased
AaPo, (alveolar-arterial pressure difference for 02) with rest
or exercise or decreased Deco (diffusing capacity of the lung
for CO)]
3. Abnormalities (described below) on conventional chest radiographs or high-resolution computed tomography (HRCT)
scans
In early stages of JPF, pulmonary function or lung imaging
studies may be normal or only slightly impaired. Patients with a
history of cigarette smoking may have coexisting chronic obstructive lung disease, which will alter the manifestations of the disease as assessed by lung function and chest imaging studies.
In the absence of a surgical lung biopsy, the diagnosis of
JPF remains uncertain. However, in the immunocompetent
adult, the presence of all of the following major diagnostic criteria as well as at least three of the four minor criteria increases the likelihood of a correct clinical diagnosis of IPF.
Major Criteria
Exclusion of other known causes of JLD, such as certain
drug toxicities, environmental exposures, and connective
tissue diseases
Abnormal pulmonary function studies that include evidence of restriction (reduced VC often with an increased
FEVi/FVC ratio) and impaired gas exchange [increased
AaPo, with rest or exercise or decreased DL~~]
Bibasilar reticular abnormalities with minimal ground
glass opacities on HRCT scans
l
Transbronchial lung biopsy or bronchoalveolar lavage
(BAL) showing no features to support an alternative diagnosis
Minor Criteria
l
l
l
l
Age>SOyr
Insidious onset of otherwise unexplained dyspnea on exertion
Duration of illness Z= 3 mo
Bibasilar, inspiratory crackles (dry or “Velcro” type in
quality)
EPIDEMIOLOGY OF IPF
Incidence and Prevalence
The precise incidence and prevalence of JPF are not known.
Previous prevalence estimates for JPF varied from 3 to 6 cases
per 100,000 in the general population (5, 6). A more recent
population-based study for all interstitial lung diseases in the
county population of Bernalillo, New Mexico revealed a prevalence of 20.2 cases per 100,000 for males and 13.2 cases per
100,000 for females with IPF (7).
Incidence estimates for JPF are quite limited. It has been
estimated at 10.7 cases per 100,000 per year for males and 7.4
cases per 100,000 per year for females (7). However, the criteria that provided the basis for these data are not precisely defined.
Sex and Age
More males have been reported with JPF than females (5, 6,
8-11). Patients with JPF are often middle aged, usually between 40 and 70 yr of age. Approximately two-thirds of patients with JPF are over the age of 60 yr at the time of presentation, with a mean age at diagnosis of 66 yr (6,9, 1 l-16). The
incidence of the disease increases with older age (6, 10). In one
study, incident cases tended to be older than prevalent cases
(9). Prevalence for adults 35 to 44 yr was 2.7 per 100,000; by
contrast, prevalence exceeded 3 7.5 per 100,000 for individuals
older than 75 yr (7). It is unclear if a syndrome similar to JPF
occurs in children; if so, it is rare (17,18).
Geographical Location and Ethnicity
JPF has no distinct geographical distribution. It is reported
worldwide in both rural and urban settings with no predilection by race or ethnicity. However, the age-adjusted mortality
rates appear higher among whites and lower among blacks
(10). The reason for this finding is unclear and likely relates to
inadequate reporting rather than to differences in the disease
course in whites compared with blacks.
There is geographic variation in the age-adjusted mortality
from pulmonary fibrosis. This variation may reflect differences in occupational or environmental exposures. In the
United States, age-adjusted mortality rates due to pulmonary
fibrosis are lowest in the Midwest and Northeast, and highest
in the West and Southeast (10). In the United Kingdom, the
highest rates of mortality secondary to JPF occur in the industrialized central areas of England and Wales (19).
Vital Statistics
Vital statistics on pulmonary fibrosis are scant and known to
be of limited value. Deaths from pulmonary fibrosis increase
with increasing age (10). The mortality rate for JPF per
100,000 population was estimated to be 3.3 in men and 2.5 in
women, with an overall rate of 3.0 in both sexes in Japan (5).
Similarly, in England and Wales, the annual number of deaths
attributed to CFA has doubled between 1979 and 1988 (1Y). A
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 161
summary of various studies reports that the mean length of
survival from the time of diagnosis varied between 3.2 and 5 yr
(20). In another study, the median survival was 28.2 mo from
the onset of respiratory symptoms (21). Death certificates underreport the diagnosis of IPF as found in studies in Britain
(15,22,23) and in the United States (24).
POTENTIAL RISK FACTORS FOR IPF
Cigarette Smoking
In case-control studies, cigarette smoking has been identified
as a potential risk factor with the odds ratio (OR) from various regions of the world ranging from 1.6 to 2.9 for the development of IPF in ever-smokers (5, 9, 25). The odds of developing IPF increased with the pack-years of smoking in a study
from the United Kingdom, but this effect was not significant
(9); while a study in the United States revealed that those with
a history of smoking for 21 to 40 pack-years had an OR of 2.3
(95% confidence interval [CI], 1.3 to 3.8) (25).
Exposure to Commonly Prescribed Drugs
One case-control study has suggested an association between
exposure to antidepressants and the risk of development of
pulmonary fibrosis (26). The significance of this finding in the
pathogenesis of IPF is unknown.
Chronic Aspiration
Chronic aspiration secondary to gastroesophageal reflux has
been implicated in development of pulmonary fibrosis (27). It
is not clear what role chronic aspiration plays in the pathogenesis of IPF.
Environmental Factors
Various environmental exposures in rural or agricultural areas
and in urban and manufacturing settings have been linked to
increasing risk of developing pulmonary fibrosis in patients
where a defined pneumoconiosis was not present (5, 6, 9, 28).
Metal dust and wood dust exposure show the most prominent
association with increased risk for developing pulmonary fibrosis independent of cigarette smoking (6, 9,28). The risk of
developing pulmonary fibrosis increases with the number of
work years of exposure. Dust containing steel, brass, lead, and
pine wood are most specifically linked to developing lung fibrosis. Exposure to solvents (29), and atopy (30) have been
suggested in the development of pulmonary fibrosis. Unfortunately, many of the studies attempting to define the environmental risks for developing pulmonary fibrosis are limited
by a reliance on the clinical diagnosis without performance
of HRCT scanning or confirmation of the presence of UIP
on lung biopsy. Therefore, these data must be considered with
caution.
Infectious Agents
Numerous viruses have been implicated in the pathogenesis of
IPF, but there remains no clear evidence for a viral etiology
(31, 32). Vergnon and coworkers found an association between Epstein-Barr virus (EBV) infection and IPF (33). EBV
viral capsid antigen has also been demonstrated in lung tissue
analyzed by immunofluorescent staining (34). A higher incidence of EBV (33-35), influenza (36-39), cytomegalovirus
(CMV) (40), and hepatitis C (41-43) infection has also been
reported in patients with IPF. The increased prevalence of
hepatitis C in patients with IPF is not greater than that in
other medical conditions (43). Parainfluenza 1 virus (Sendai)
(31), human immunodeficiency virus 1 (HIV-l) (44), measles
virus (45), parainfluenza 3 virus (46), herpesvirus 6 (47), My-
2000
coplustna (48), and legionnaires’ disease (49) have also been
implicated as potential participants in the pathogenesis of IPF.
However, these reports mainly show evidence of nonspecific
pulmonary fibrosis and it is unclear the extent to which these
sequelae mimic IPF.
Genetic Predisposition to IPF
Hereditary factors may contribute to the risk of developing
IPF (50-54) but no specific genetic markers have been identified (55). The most compelling evidence for participation of
genetic factors is descriptions of familial cases of IPF. Familial
IPF (FPF) is defined as at least two members of a primary biological family (parent, child, sibling) having clinical features
of IPF that are confirmed histologically (55, 56). Review of
medical records of family members with apparent breathing
problems may actually identify more families with familial
pulmonary fibrosis and other inherited ILDs. Familial IPF is
probably inherited as an autosomal dominant trait with variable penetrance (54). Males and females are equally affected.
There has been no clear association with human leukocyte antigen (HLA) (53, 57-59). Several investigators have reported
an association between IPF and a,-antitrypsin inhibition (Pi)
alleles present on chromosome 14 (60-62).
APPROACH TO THE DIAGNOSIS OF IPF
The differential diagnosis of ILD is large and includes a heterogeneous group of acute and chronic processes. There have
been many reviews that describe the differential diagnosis of
ILD and provide a diagnostic algorithm useful in evaluating a
patient with ILD (3). The diagnostic process for a patient with
diffuse parenchymal lung disease must start with the elicitation of a thorough and extensive medical history that should
include review of symptoms or signs suggestive of a systemic
disorder, occupational and environmental exposures, use of
medications and drugs, and family medical history.
History and Physical Examination
While it is essential to make an accurate diagnosis for appropriate therapeutic interventions, the physician must realize that
the key diagnostic procedure in the evaluation of ILD is a thorough clinical assessment. The patient’s age at the time of presentation may provide useful clues-for example, IPF is almost
always an adult disorder, typically occurring in patients beyond
50 yr of age; sarcoidosis is more commonly seen in young and
middle-aged adults, although it can manifest in the elderly patient; pulmonary histiocytosis X typically occurs in young cigarette smokers; respiratory bronchiolitis-associated interstitial
lung disease (RBILD) occurs predominantly in heavy cigarette
smokers of all ages; lymphangioleiomyomatosis (LAM) occurs
predominantly in women who are premenopausal and is rare.
IPF usually presents insidiously, with the gradual onset of a
nonproductive cough and dyspnea. Dyspnea is usually the
most prominent and disabling symptom. It is usually progressive and in most patients it is reported to have been present
for > 6 mo before presentation. Patients may also complain of
paroxysmal dry cough that is refractory to antitussive agents.
On physical examination, crackles are detected on chest
auscultation in more than 80% of patients. These are typically
“dry,” end-inspiratory, and “Velcro” in quality, and are most
prevalent in the lung bases. With progression of the disease,
rales extend toward the upper lung zones. Clubbing is noted in
25 to 50% of patients (11,15). Cyanosis, car pulmonale, an accentuated pulmonic second sound, right ventricular heave,
and peripheral edema may be observed in the late phases of
the disease (11,20).
American Thoracic Society
Extrapulmonary involvement does not occur, but weight
loss, malaise, and fatigue may be noted. Fever is rare, and its
presence suggests an alternative diagnosis. Symptoms or signs
suggestive of a connective tissue disease (joint pains or swelling, musculoskeletal pain, weakness, fatigue, fever, photosensitivity, Raynaud’s phenomenon, pleuritis, dry eyes, dry mouth)
should be carefully elicited.
Laboratory and Serological Tests
The routine laboratory evaluation of a patient suspected of
having IPF is often not helpful except to “rule out” other
causes of diffuse parenchymal lung disease. Polycythemia is
rare despite the frequent presence of chronic hypoxemia. An
elevated erythrocyte sedimentation rate and hypergammaglobulinemia may be found but are nondiagnostic. Elevation
of lactate dehydrogenase (LDH) may be noted but is a nonspecific finding common to pulmonary disorders (e.g., alveolar
proteinosis, idiopathic pulmonary fibrosis). An increase in the
angiotensin-converting enzyme (ACE) level, or the presence
of antibodies to organic antigens or anti-neutrophil cytoplasmic antibodies, although nondiagnostic, may be helpful in suggesting alternative diagnoses.
Positive circulating anti-nuclear antibodies (ANAs) or
rheumatoid factor occur in 10 to 20% of patients with IPF, but
rarely are titers high. The presence of high titers (> 1:160)
would suggest the presence of a connective tissue disease (6370). Rarely, a patient may present with the clinical features of
IPF and later develop a defined connective tissue disease. In
these cases, the term IPF is not maintained since the illness is
secondary to the underlying, previously undiagnosed connective tissue disease (e.g., “rheumatoid lung”). These various
tests do not correlate with the extent or activity of pulmonary
fibrosis, and do not predict therapeutic responsiveness (20).
The electrocardiogram is usually normal in the absence of
pulmonary hypertension or concurrent cardiac disease.
Chest Radiograph
Virtually all patients with IPF have an abnormal chest radiograph at the time of presentation (11). Indeed, basal reticular
opacities are often visible on previous chest radiographs in retrospect for several years before the development of symptoms. In individuals with such asymptomatic abnormalities, investigation by physiologic evaluation or by high-resolution CT
scanning could lead to earlier detection and treatment of IPF.
Conversely, a normal chest radiograph cannot be used to exclude microscopic evidence of UIP on lung biopsy (71, 72).
However, the HRCT scan will likely show evidence of disease
in most of the cases with a normal chest radiograph.
Peripheral reticular opacities, most profuse at the lung
bases, are characteristic findings on the chest radiograph of
patients with IPF (73). These opacities are usually bilateral,
often asymmetric, and are commonly associated with decreased lung volumes. Confluent alveolar opacities are rarely
visible on the chest radiograph of patients with IPF, and, if
present, suggest some other diagnosis, such as DIP or BOOP
(73, 74). Patients with combined emphysema and IPF may
have preserved or increased lung volumes, and may have upper lobe oligemia (i.e., apparent reduction in blood vessels).
The differential diagnosis of the basal reticular pattern includes asbestosis and connective tissue diseases (such as scleroderma or rheumatoid arthritis). When a “confident” diagnosis of IPF is made on the basis of the chest radiograph
(compared with an “uncertain” or “unlikely” diagnosis of IPF),
it is correct in 48% (75) to 87% (76,77) of cases. Radiographic
evidence of pleural disease or lymphadenopathy is not usually
found in IPF.
649
Given the indolent course of IPF, the clinical utility and
optimal timing of follow-up chest radiographs are unclear.
Radiographs are indicated if clinical deterioration occurs, to
assess progression of disease, or to identify superimposed infection or malignancy. The profusion of lung opacities may be
quantified visually, using a modification of the International
Labor Organization (ILO) criteria for pneumoconiosis (78).
However, this technique is time-consuming, and has not been
proven to be clinically useful (79).
High Resolution CT Scanning
High-resolution CT (HRCT) scanning has changed the diagnostic evaluation of patients with IPF (72, 80, 81). The technique of high-resolution CT allows detailed evaluation of
the lung parenchyma by using l- to 2-mm-thick slices, with a
reconstruction algorithm that maximizes spatial resolution.
HRCT allows earlier diagnosis of IPF, helps to narrow the differential diagnosis based on the CT pattern, and allows the
identification of the extent of associated emphysema (72, 82,
83). HRCT can also help to increase the level of diagnostic
confidence for IPF, when the clinical or radiologic features are
uncertain.
Radiologic pattern in IPF. The HRCT pattern of IPF commonly shows patchy, predominantly peripheral, subpleural,
bibasal reticular abnormalities. There may also be a variable
amount of ground glass opacity that is usually limited in extent. In areas of more severe involvement there is often traction bronchiectasis and bronchiolectasis and/or subpleural
honeycombing.
Accuracy of HRCT diagnosis. Studies that have evaluated
the ability of CT scanning to accurately diagnose IPF have
found that CT increases the level of diagnostic confidence
compared with the chest radiograph. The accuracy of a confident diagnosis of UIP made on HRCT by a trained observer
appears to be about 90% (75-77, 84). However, because a
confident diagnosis of IPF is made by HRCT evaluation in
only about two-thirds of patients with histologic UIP (85)
about one-third of cases of UIP will be missed by relying on
CT diagnosis alone. Less experienced observers are substantially less accurate than experienced observers (75).
Differential diagnosis of the HRCT pattern. Connective tissue diseases (particularly scleroderma and rheumatoid arthritis) (86, 87) and asbestosis (88-91) are commonly similar in
CT appearance to IPF, except for the presence of parenchyma1 bands of fibrosis and pleural plaques in patients with asbestosis. Patients with subacute or chronic hypersensitivity
pneumonitis can have similar reticular opacity or honeycombing, but often lack the bibasilar predominance seen in IPF
(84). IPF may also be mimicked on CT by sarcoidosis (92) or
idiopathic BOOP (77).
Extensive ground glass opacity on CT of the lung (2 30%
of lung is involved) should prompt consideration of another
diagnosis rather than IPF, particularly desquamative interstitial pneumonitis (DIP) (93). Similar ground glass opacification, without basal or peripheral predominance, may be found
in patients with respiratory bronchiolitis-interstitial lung disease (94) hypersensitivity pneumonitis (84, 95) idiopathic
BOOP (77) or nonspecific interstitial pneumonia (NSIP) (96).
The presence of centrilobular nodules, middle and upper lobe
lung predominance, and absence of honeycombing favor hypersensitivity pneumonitis over IPF (84). Most importantly,
the CT features must be interpreted in conjunction with a
complete clinical evaluation.
Role of HRCT in determining disease activity. HRCT has
been proposed as a technique for determining the “activity” of
IPF (97). The CT finding of ground glass opacity (also called
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 161
ground glass attenuation or hazy increase in lung density) refers to the presence of a diffuse homogeneous increase in density of the lung. When this finding occurs in association with
reticular lines, and dilated bronchi or bronchioles (traction
bronchiectasis or bronchiolectasis), it always indicates lung fibrosis. In conditions other than IPF, isolated ground glass density is usually associated with inflammatory cells in the alveolar septum or alveolar lumen (i.e., alveolitis) (98).
The ground glass opacity seen on HRCT in some patients
with IPF can be associated with alveolar inflammation (97),
but is predominantly associated with patchy fibrotic thickening of alveolar septa, and intraalveolar granulation tissue (99).
Some studies have suggested that ground glass attenuation
predicts physiologic improvement after steroid treatment (81).
Ground glass opacity on CT often regresses on treatment in
patients who have histologic DIP, but may not decrease as
readily in those with histologic UIP (100). An area of ground
glass opacity may progress to reticular opacity or honeycombing on follow-up evaluation (79). Patients with predominant
reticular opacity or honeycombing usually progress despite
treatment (81, 100-103). The extent of lung fibrosis on CT is
an important predictor of survival (103).
Role of HRCT in defining disease extent. CT is increasingly
used for quantification of disease extent. Subjective, semiquantitative assessment of disease extent by CT shows moderate interobserver variability. This semiquantitative assessment
correlates with evidence of physiologic impairment (104,105).
One study showed that the extent of overall lung involvement
and the extent of ground glass pattern in the HRCT scans
show a moderate correlation only with FVC and arterial Po2
at peak exercise (103). Use of parameters derived from the
digital CT data set may provide a more objective measure of
disease extent (106).
For detection of early or mild infiltrative lung disease, HRCT
is clearly more sensitive than the chest radiograph (107). However, in the early stages of any lung disease, including IPF, the
degree of parenchymal infiltration may be too slight to cause
any CT abnormality (72). Indeed, it has been shown that patients with biopsy-proven hypersensitivity pneumonitis (107),
sarcoidosis (log), asbestosis (109), and IPF (72) may have normal high-resolution CT studies. Therefore, although it is quite
rare, a normal HRCT cannot be used to exclude infiltrative
lung disease.
Other Imaging Techniques
The extreme inhomogeneity of magnetic susceptibility in the
lung hampers the use of magnetic resonance to image the lung
parenchyma. It may in future be useful as a tool for discriminating between lung inflammation and established fibrosis
(110). Gallium imaging is not of any proven value for evaluation of IPF. Aerosols containing “““Tc-DTPA, a hydrophilic
agent, are cleared more rapidly when there is increased capillary permeability, and may provide an index of lung inflammation (111-l 13). However, the clinical role of this agent remains unproven.
Pulmonary Function Testing
The typical findings of pulmonary function tests are consistent
with restrictive impairment (reduced vital capacity [VC] and
total lung capacity [TLC]) by body plethysmography (114).
Unless a complicating airways disease occurs, isovolume flow
rates are well maintained. The DL~~ corrected for hemoglobin
is reduced frequently and the decline in DL~~ may precede abnormalities in lung volume. The maximal breathing capacity is
usually normal. The resting arterial blood gases may be normal or reveal hypoxemia (secondary to ventilation and perfu-
2000
sion mismatch) and respiratory alkalosis, and these abnormalities may be elicited or accentuated by exercise.
Lung volumes. The lung volumes (TLC, functional residual
capacity [FRC], and residual volume [RV]) are reduced at
some point in the course of disease in all patients with IPF.
Early on, or more commonly in patients with superimposed
chronic obstructive pulmonary disease, the lung volumes may
be normal. Lung volumes are higher in smokers compared
with never-smokers with IPF (115).
Pressure-volume studies often yield a curve that is shifted
downward and to the right, consistent with a stiff noncompliant lung. In general, as the disease progresses, lung compliance decreases and lung volumes fall (116-122). Smokers have
a shift of the pressure-volume curve upward and to the left
and the transpulmonary pressure at any given lung volume is
significantly lower than in nonsmokers with IPF. As a result,
the coefficient of elastic retraction of the lungs is lower in
smokers than in nonsmokers with IPF (115).
Airways mechanics. Patients with IPF are tachypneic; they
develop more rapid shallow breaths as the disease progresses,
and therefore the work of breathing is increased (123, 124).
This rapid respiratory rate is felt to be secondary to altered
mechanical reflexes, because of the increased elastic load and/or
vagal mechanisms, since no defined chemical basis for the hyperventilation has been identified (125-132). Expiratory flow
rates, forced expiratory volume in 1 s (FEV,), and forced vital capacity (FVC) are often decreased because of the reduction in lung volume, but the FEV,-to-FVC ratio is maintained
or increased in IPF. However, because of the increased static
elastic recoil found in these patients, flow rates when compared with lung volumes are often increased. Functional and
pathologic alterations consistent with small airways disease
have been described in patients with various interstitial pulmonary diseases, including IPF (116, 118, 133, 134). However,
chronic airflow obstruction has been reported exclusively
among smokers with IPF (123,124,135).
Gas exchange at rest and during exercise. The DL~~ (corrected for hemoglobin level) is reduced and may actually precede the reduction of lung volume. The reduction in the DL~~
is probably caused both by a contraction of the pulmonary
capillary volume and by ventilation and perfusion abnormalities. The resting arterial blood gases may be normal initially or
may reveal mild hypoxemia and respiratory alkalosis. The major cause of resting hypoxemia is ventilation and perfusion
mismatching and is not due to either impaired oxygen diffusion, as was originally suspected, or by anatomic shunts. With
exercise, the alveolar-arterial O2 gradient (AaPo*) widens, and
the arterial O2 pressure (PaoX) and arterial O2 saturation
(SaoJ fall. During exercise, 20 to 30% of the exercise-induced
widening of the AaPo* may be caused by some impairment of
oxygen diffusion. Importantly, the abnormalities identified at
rest do not accurately predict the magnitude of the abnormalities that may be seen with exercise. Although these abnormalities can be assessed by oximetry saturation, it has been demonstrated that this method may not yield as dramatic or
significant a change as that obtained by arterial blood gases.
Thus, formal cardiopulmonary exercise testing is more sensitive than resting physiologic testing in the detection of abnormalities in O2 transfer, and exercise gas exchange has been
demonstrated to be a sensitive parameter for monitoring the
clinical course (122).
Patients with IPF increase their minute ventilation during
exercise primarily by increasing their respiratory frequency.
This method of increase differs from normal subjects in whom
increased ventilation during mild exercise occurs by an increase in the VT rather than respiratory rate. Thus, patients
American Thoracic Society
with IPF have an elevated minute ventilation during exercise
that is in part related to the increase in dead space (VD) ventilation. As well, the ratio of VD to Vr is increased at rest and is
maintained or decreases with exercise. On occasion, the VD to
VT ratio may increase in interstitial lung disorders that have a
prominent pulmonary vascular component, such as scleroderma. In patients with IPF, an increase in the VDIVT ratio
should raise concern about pulmonary vascular disease, especially chronic pulmonary emboli, or associated emphysema.
Pulmonary hemodynamics. Pulmonary hypertension rarely
occurs at rest in patients with early IPF. Nevertheless, pulmonary hypertension during exercise is common even during the
early stages of IPF. When the VC is less than 50% of predicted
or the DL~~ falls below 45% of predicted, pulmonary hypertension at rest can be expected (136). In advanced pulmonary
fibrosis, auscultatory findings consistent with pulmonary hypertension are present. The mean pulmonary artery pressure
at rest ranges between 23 and 28 mm Hg and rarely exceeds 40
mm Hg. A resting mean pulmonary artery pressure greater
than 30 mm Hg is associated with a poor prognosis.
The exact mechanism(s) for the development of pulmonary
hypertension in IPF is unknown. The pulmonary artery wedge
pressure remains normal in IPF, and car pulmonale is a late
sequela. It has been demonstrated that oxygen therapy at rest
and during exercise improves pulmonary hemodynamics and
likely improves exercise capacity and prognosis. However, few
data exist on the value of vasodilator therapy in the treatment
of pulmonary hypertension in the interstitial lung diseases.
Sleep disturbance. Patients with IPF, especially those with
daytime Saoz of less than 90% and/or a history of snoring during sleep, have been shown to develop sleep disturbances.
These patients were found to have reduced rapid eye movement (REM) sleep, lighter and more fragmented sleep, and
hypoxemia during REM sleep. Severe hypoxemia occurred
even in the absence of obstructive or actual sleep apnea or
changes in breathing pattern. Patients with tachypnea while
awake maintain their tachypnea during sleep. This maintenance
of rapid breathing during sleep suggested that the reflexes
causing the rapid shallow breathing were active during the
sleep phase as well. Thus, although definitive studies are lacking, identification and correction of the sleep disturbance and
the use of supplemental oxygen during sleep are recommended
because these may reduce morbidity and improve patient survival, especially regarding the pulmonary hypertension and
car pulmonale that develop in patients with IPF (137,138).
Bronchoalveolar Lavage
Bronchoalveolar lavage (BAL) has been enormously helpful
in elucidating the key immune effector cells driving the inflammatory response in IPF (139, 140). Increases in polymorphonuclear leukocytes (PMNs), neutrophil products, eosinophils, eosinophil products, activated alveolar macrophages,
alveolar macrophage products, cytokines, growth factors for
fibroblasts, and immune complexes have been noted in BAL
of patients with IPF.
Despite its value as a research tool, the diagnostic usefulness of BAL in IPF is limited. BAL may substantiate a variety
of alternative specific diagnoses provided appropriate laboratory studies are performed to identify the key features (e.g.,
malignancy, infections, eosinophilic pneumonia, pulmonary
histiocytosis X). In addition, the pattern of inflammatory cells
identified may be helpful in narrowing the differential diagnosis of fibrosing interstitial pneumonias but is not diagnostic of IPF.
An increase in neutrophils (levels > 5%) is noted in 70 to
90% of patients, an associated increase in eosinophils (levels
651
> 5%) is apparent in 40 to 60% of patients, and an additional
increase in lymphocytes is noted in 10 to 20% of patients (21).
However, these findings are seen in a wide variety of fibrosing
lung conditions other that IPF. A lone increase in lymphocytes
is uncommon in IPF (< 10% of patients), so when present,
another disorder should be excluded (e.g., granulomatous infectious disease, sarcoidosis, hypersensitivity pneumonitis, idiopathic bronchiolitis obliterans organizing pneumonia [BOOP],
nonspecific interstitial pneumonia [NSIP], or lymphocytic interstitial pneumonia [LIP]).
Provided its limitations are kept in mind, there appears to
be a place for BAL in the evaluation of diffuse lung disease.
The presence of a BAL neutrophilia increases the likelihood
of an underlying fibrosing process (IPF, the fibrosing alveolitis
of rheumatological disease, asbestosis, or fibrotic sarcoidosis).
A BAL lymphocytosis is more suggestive of NSIP, granulomatous disease, or a drug-induced lung disease. Further BAL
may reveal a number of alternative diagnoses, e.g., malignancy, infections, eosinophilic pneumonia, pulmonary histiocytosis X (with CD1 immunostain), or occupational dust exposure.
The clinical value of BAL to stage or monitor IPF is limited. Increases in the percentage of neutrophils or eosinophils
(or both) in BAL fluid have been associated with a worse
prognosis in some but not all studies (12). BAL lymphocytosis,
found in fewer than 20% of patients with IPF, has been associated with a more cellular lung biopsy, less honeycombing, and
a greater responsiveness to corticosteroid therapy (14). However, these relationships are too inconsistent in individual patients for BAL to be used as a reliable prognostic guide. Given
its expense and invasiveness, serial bronchoscopy with BAL
cannot be justified in the clinical management of patients with
IPF. Cellular profiles obtained at the time of BAL as part of
the initial diagnostic evaluation may be prognostically useful,
but only in laboratories with a specific expertise in BAL analysis and where appropriate normal values and ranges have been
established (14, 139, 141-148).
Lung Biopsy
Usual interstitial pneumonia (UIP) is the histopathological
pattern that identifies patients with IPF. Surgical lung biopsy,
either open thoracotomy or preferentially by video-assisted
thoracoscopy, provides the best tissue samples to distinguish
UIP from other forms of idiopathic interstitial pneumonia and
to exclude other processes that mimic IPF when identified in
the setting of ILD of unknown etiology. The histopathologic
patterns of desquamative interstitial pneumonia (DIP), respiratory bronchiolitis associated with interstitial lung disease
(RBILD), nonspecific interstitial pneumonia (NSIP), lymphoid interstitial pneumonia (LIP), acute interstitial pneumonia (AIP), and BOOP are considered separate entities and are
to be excluded from the group of patients with IPF. Thus, surgical lung biopsy is recommended in patients with suspected
IPF and without contraindications to surgery. This recommendation is important in any patient with clinical or radiologic
features that are not typical for IPF. In the instances when
atypical clinical, radiographical, or physiological features of
IPF are encountered, it has been shown that histopathological
patterns other than UIP are more likely to be found, thereby
often defining a process with a different prognosis or resulting
in alternative approaches to management. The potential risks
and cost associated with surgical lung biopsy need to be balanced against the accuracy of a clinical diagnosis, the likelihood of identifying a more treatable form of ILD, and the efficacy of the treatment (149). The potential benefits of surgical
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
lung biopsy may be outweighed by increased risk for surgical
complications (e.g., age > 70 yr, extreme obesity, concomitant
cardiac disease, extreme impairment in pulmonary function).
Video-assisted thoracoscopic (VATS) lung biopsy is the preferred technique, as this has been associated with less morbidity, less prolonged chest tube drainage, and reduced length of
hospital stay compared with open lung biopsy (150-1.52).
Many clinicians believe transbronchial lung biopsies (TBBs)
may be acceptable in the diagnosis of some processes that may
mimic IPF (3, 153). Clearly, transbronchial biopsies are not
helpful in making the diagnosis of UIP (101, 107). Although
TBBs are abnormal in many cases, they do not confirm UIP.
Also, because of the small sample size (2 to 5 mm), TBBs
should not be used to assess the degree of fibrosis or inflammation. TBB may exclude UIP by identifying an alternative
specific diagnosis in the right clinical setting or with the use of
special histopathological methods or stains, for example, malignancy, infections, sarcoidosis, hypersensitivity pneumonitis,
bronchiolitis obliterans organizing pneumonia, eosinophilic
pneumonia, or pulmonary histiocytosis X.
Open or video-assisted thoracoscopic surgical lung biopsy
is performed in a minority of patients with chronic ILD, likely
reflecting the pessimism that findings on lung biopsy will alter
the proposed treatment plan (150). A review of 200 patients
with IPF in the United Kingdom showed that transbronchial
or open lung biopsies were performed in only 33% and 7.5%
of patients, respectively; the diagnosis of IPF was made on
clinical grounds in most cases (153). Clinical practice in the
United States and other countries often mirrors this approach
of relying largely on clinical and radiological features to make
the diagnosis of IPF (154, 1.55). In most clinical series describing patients with presumed IPF, open or thoracoscopic lung
biopsies were performed only in a minority of patients and
many of these reports included patients with connective tissue
disease or occupational exposures known to be associated
with development of ILD (7, 8, 11, 12, 15, 21, 22, 24, SO, 144,
153, 154, 156-164). As discussed above, most studies show that
expert observers will make a confident CT diagnosis of UIP in
only about two-thirds of patients with histologic UIP (85).
Therefore, one-third of cases of UIP would be missed by relying on CT diagnosis alone.
Histopathological assessment. The gross morphologic findings in IPF range from a normal appearance in early cases to
diffuse honeycombing in the later stages of the disease process. Disease involvement is usually heterogeneous and worse
in the lower lobes. A subpleural, peripheral, and paraseptal
distribution of fibrosis is often seen. Areas of mildly involved
or even normal pulmonary parenchyma may be interspersed
throughout a background of extensive fibrosis and honeycombing.
Usual interstitial pneumonia (UIP) is the pathological abnormality essential to the diagnosis of IPF. The histologic hallmark and chief diagnostic criterion is a heterogeneous appearance at low magnification with alternating areas of normal
lung, interstitial inflammation, fibrosis, and honeycomb change.
These histological changes affect the peripheral subpleural parenchyma most severely. The interstitial inflammation is usually patchy and consists of an alveolar septal infiltrate of lymphocytes and plasma cells, associated with hyperplasia of type
2 pneumocytes. The fibrotic zones are composed mainly of
dense collagen, although scattered foci of proliferating fibroblasts (so-called “fibroblastic foci”) are a consistent finding.
Areas of honeycomb change are composed of cystic fibrotic
air spaces that are frequently lined by bronchiolar epithelium
and filled with mucin. Smooth muscle hyperplasia is commonly seen in areas of fibrosis and honeycomb change. Pa-
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tients who are biopsied during an accelerated phase of their
illness may show a combination of UIP and diffuse alveolar
damage.
There is no single histologic finding that has shown a consistent correlation with treatment response or prognosis in
UIP. Several investigators have shown a weak positive correlation between the degree of alveolar septal inflammation and
steroid responsiveness, and a negative correlation between extent of fibrosis and response to steroid therapy. It is unclear if
these studies included cases of DIP, RBILD or NSIP in their
analysis.
The pathological differential diagnosis of UIP includes the
following (16.5, 166):
I. Desquamative interstitial pneumonia (DIP) (93, 100, 167,
168). DIP is a rare entity (incidence, < 3% of all ILDs). It affects cigarette smokers in their fourth or fifth decade of life.
Most patients present with a subacute (weeks to months) illness characterized by dyspnea and cough. The chest radiograph shows less severe changes compared with IPF and may
be normal in up to 20% of cases. The chest radiograph and
HRCT scan pattern show diffuse ground glass opacity in the
middle and lower lung zones. Lung function testing shows a
restrictive pattern with reduced DL~~ and hypoxemia on blood
gas analysis. Lung biopsy reveals a uniform, diffuse, intraalveolar macrophage accumulation. The macrophage accumulation may be accentuated around respiratory bronchioles; however, it extends diffusely throughout the lung parenchyma.
There is little fibrosis with only mild or moderate thickening
of alveolar walls. Unlike UIP, there is no scarring fibrosis
causing remodeling of the lung architecture. Fibroblastic foci
are absent or inconspicuous and the fibrous connective tissue
that is present appears at about the same age. Interstitial inflammation is usually mild in extent and severity and consists
of lymphocytes and a few plasma cells. Clinical recognition of
DIP is important because the process is associated with a better prognosis than IPF, with an overall survival of about 70%
after 10 yr.
2. Respiratory bronchiolitis-associated inter.stitial lung disease
(RBILD) (94, 169-171). Like DIP, RBILD is a clinical syndrome found in current or former cigarette smokers. The clinical
presentation resembles those of patients with other ILDs: cough
and breathlessness with exertion, crackles on chest examine.
Diffuse, fine reticular, or nodular interstitial opacities are found
on chest radiograph usually with normal-appearing lung volumes. HRCT scanning often reveals hazy opacities. A mixed obstructive-restrictive pattern is common on lung function testing.
An isolated increase in RV may be found. Arterial blood gases
show mild hypoxemia. On lung biopsy, RBILD is defined by the
presence of pigmented macrophages within the lumens of respiratory bronchioles. The changes are patchy at low magnification
and have a bronchiolocentric distribution. Respiratory bronchioles, alveolar ducts, and peribronchiolar alveolar spaces contain
clusters of these dusty brown macrophages accompanied by a
patchy submucosal and peribronchiolar infiltrate of lymphocytes
and histiocytes. Peribronchiolar fibrosis is also seen and expands
to contiguous alveolar septa, which are lined by hyperplastic
type 2 cells and cuboidal bronchiolar-type epithelium. The combination of alveolar septal thickening, epithelial hyperplasia, and
pigmented intralumenal macrophages mimicks the appearance
of DIP. The clinical course and prognosis of respiratory bronchiolitis are unknown but appear substantially better than IPF.
Smoking cessation is important in the resolution of these lesions.
3. Nonspec$ic interstitial pneumonius (NSIP) (96, 172,
173). NSIP refers to a histologic appearance in ILD that does
not conform to the previously established histologic patterns.
American Thoracic Society
The clinical presentation is similar to IPF. Cough and dyspnea
are present for months to years. Chest radiographic findings
show primarily lower zone reticular opacities. Bilateral patchy
opacities can also be seen. HRCT shows bilateral symmetric
ground glass opacities or bilateral air space consolidation. It is
extremely important that the pathologist not use “UIP” to refer to any nonclassifiable chronic interstitial pneumonia (172).
The main histologic feature of NSIP is the homogeneous appearance of either inflammation or fibrosis as opposed to the
heterogeneity seen in the other interstitial pneumonias. The
changes are temporally uniform but the process may be patchy
with intervening areas of unaffected lung. Honeycomb areas
are rare. Unlike patients with UIP, the majority of patients
with NSIP have a good prognosis, with most showing improvement after treatment with corticosteroids. Most cases of NSIP
are of unknown etiology and are not associated with other
processes, however, others appear to have an ill-defined connective tissue disease, drug-induced ILD, or chronic hypersensitivity pneumonitis as an underlying feature. There is an estimated 1520% mortality in 5 yr.
4. Acute interstitial pneumonia (Hamman-Rich syndrome)
(174-176). Acute interstitial pneumonia (AIP) is a rare fulminant form of lung injury that presents acutely (days to weeks
from onset of symptoms), usually in a previously healthy individual. The clinical signs and symptoms are most often fever,
cough, and shortness of breath. Routine laboratory studies are
nonspecific and generally not helpful. Diffuse, bilateral, airspace opacification is seen on chest radiograph. CT scans show
bilateral, patchy, symmetric areas of ground glass attenuation.
Bilateral areas of airspace consolidation may also be present.
A predominantly subpleural distribution may be seen. These
radiographic findings are similar to those seen in acute respiratory distress syndrome (ARDS). Most patients have moderate to severe hypoxemia and develop respiratory failure. The
diagnosis of AIP requires the presence of a clinical syndrome
of idiopathic ARDS and pathological confirmation of organizing diffuse alveolar damage (DAD). Lung biopsies from patients with AIP show histologic features identical to those of
the exudative, proliferative, and/or fibrotic phases of DAD.
The lung biopsy typically shows diffuse involvement although
there may be variation in the severity of the changes among
different histologic fields. The exudative phase shows edema,
hyaline membranes, and interstitial acute inflammation. As
the lesion progresses, type 2 pneumocyte hyperplasia becomes
prominent. The pneumocytes may show cytologic atypia. Loose
organizing fibrosis is mostly seen within alveolar septa, but it
may also be seen within airspaces and this may be a prominent
feature in more than one-third of cases. The connective tissue
changes appear at about the same age. If the patient survives
the lungs may resolve to normal. The lungs may also progress
to end-stage honeycomb fibrosis. The mortality from AIP is
high (> 60%) with the majority of patients dying within 6 mo
of presentation. The main treatment is supportive care.
5. Idiopathic hronchiolitis ohliterans with organizing pneumonia (idiopathic BOOP) (73, 177-183). Idiopathic BOOP is
a clinicopathological syndrome of unknown etiology. The disease onset occurs usually in the fifth and sixth decade and affects men and women equally. Almost three-fourths of the patients have their symptoms for less than 2 mo. A fluhke illness,
characterized by cough, fever, malaise, fatigue, and weight
loss, heralds the onset of idiopathic BOOP in two-fifths of the
patients. Inspiratory crackles are frequently present on chest
examination. Routine laboratory studies are nonspecific. Pulmonary function is usually impaired, with a restrictive defect
being most common. Resting and exercise arterial hypoxemia
is a common feature. The roentgenographic manifestations
653
are quite distinctive. Bilateral, diffuse alveolar opacities in the
presence of normal lung volume constitute the characteristic
radiographic appearance in patients with idiopathic BOOP. A
peripheral distribution of the opacities, similar to that thought
to be “virtually pathognomonic” for chronic eosinophilic pneumonia, is also seen in idiopathic BOOP. Rarely, the alveolar opacities may be unilateral. Recurrent and migratory pulmonary opacities are common. Irregular linear or nodular
interstitial infiltrates or honeycombing are rarely seen at presentation. HRCT scans of the lung reveal patchy airspace consolidation, ground glass opacities, small nodular opacities and
bronchial wall thickening and dilation. These patchy opacities
occur more frequently in the periphery of the lung and are often in the lower lung zone. The CT scan may reveal much
more extensive disease then is expected by review of the plain
chest X-ray. The histopathologic lesions characteristic of idiopathic BOOP include an excessive proliferation of granulation
tissue within small airways (proliferative bronchiohtis) and alveolar ducts associated with chronic inflammation in the surrounding alveoli. There are several other key features: there is
a uniform, recent temporal appearance to the changes; the
lung architecture is not severely disrupted; the distribution is
patchy and peribronchiolar; the lesions are usually located
within the airspace; foamy macrophages are common in the alveolar spaces, presumably secondary to the bronchiolar occlusion; the intralumenal buds of granulation tissue consist of
loose collagen-embedding fibroblasts and myofibroblasts that
extend from one alveolus to the adjacent one through the
pores of Kohn, giving rise to the characteristic “butterfly” pattern; the bronchiolar lesions are secondary to intralumenal
plugs of granulation tissue, always in association with plugs in
the alveolar ducts and alveolar spaces; severe fibrotic changes,
such as honeycombing, are unusual at the time of diagnosis:
and giant cells are rare or absent, no granuloma or vasculitis is
present. Corticosteroid therapy results in clinical recovery in
two-thirds of the patients.
6. Lymphocytic interstitial pneumonitis (L/f) (184, 185).
LIP is an uncommon cause of interstitial lung disease. It is distinguishable from DIP and UIP by the presence of monotonous sheets of lymphoplasmacytic cells that expand the interstitium. In addition. lymphocytes are found within alveolar
spaces and lymphoid aggregates are distributed along lymphatic routes. Lymphocyte aggregates also appear in an angiocentric location. Other histologic features include type 2 epithelial cell hyperplasia, the presence of interstitial mononuclear
cells, and the formation of interstitial noncaseating granulomas. The majority of cases are associated with some form of
dysproteinemia (either a monoclonal or polyclonal gammopathy) or are found in association with Sjogren’s syndrome (primary or secondary) or acquired immune deficiency syndrome
(AIDS). The chest radiograph and HRCT are nonspecific, indicating bilateral, predominantly low-zone mixed alveolarinterstitial infiltrates. If a pleural effusion or mediastinal lymphadenopathy are present, the possibility of a low-grade lymphoma should be considered. Because of this tendency to
progress to lymphoma most experts no longer include LIP
among the idiopathic interstitial pneumonias.
7. Pulmonary histiocytosis X (186-l 90). Pulmonary histiocytosis X of the lung is a rare, smoking-related diffuse lung
disease that primarily afflicts young adults between the ages of
20 and 40 yr. The clinical presentation is variable, from an
asymptomatic state (approximately 16%) to a rapidly progressive condition. The most common clinical manifestations at
presentation are cough, dyspnea, chest pain, weight loss, and
fever. Pneumothorax occurs in about 25% of patients and is
occasionally the first manifestation of the illness. Hemoptysis
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
and diabetes insipidus are rare manifestations. The physical
examination is usually normal and routine laboratory studies
are not helpful. The radiographic features vary depending on
the stage of the disease. The combination of ill-defined or stellate nodules (2-10 mm in size), reticular or nodular opacities,
upper zone cysts or honeycombing, preservation of lung volume, and costophrenic angle sparing are felt to be highly specific for pulmonary histiocytosis X. CT lung scanning that reveals the combination of nodules and thin-walled cysts is virtually
diagnostic of pulmonary histiocytosis X. Physiologically, the
most prominent and frequent pulmonary function abnormality reported is a markedly reduced DL~~, although varying degrees of restrictive disease, airflow limitation, and diminished
exercise capacity are described. Histiocytosis X is frequently
associated with a “DIP-like” or RB pattern due to the strong
association with cigarette smoking. However, histiocytosis X is
predominantly an interstitial lesion characterized by the presence of centrally scarred stellate nodules seen well at low magnification, containing a polymorphic inflammatory infiltrate.
Diagnosis of histiocytosis X is predicated on recognition of
characteristic Langerhans cells within the inflammatory infiltrate in the appropriate histological context. Discontinuance
of smoking is the key treatment, resulting in clinical improvement in 33% of the subjects. Most patients with pulmonary
histiocytosis X suffer persistent or progressive disease. Death
due to respiratory failure occurs in - 10% of patients.
8. A pattern of interstitial inflammation and fibrosis sometimes indistinguishable from UIP can occur in patients with asbestosis, connective tissue disease, chronic hypersensitivity
pneumonitis, and certain drug-induced lung diseases. A histologic diagnosis of asbestosis requires demonstration of the offending fibers (usually in the form of ferruginous asbestos
bodies) in the tissue specimen. Comrective tissue disease,
chronic hypersensitivity pneumonitis, and drug-induced lung
diseases are distinguished by their clinical, serological, or radiographic manifestations.
9. Rarely, there are biopsies that cannot be classified into
any of the recognized patterns, i.e., UIP, DIP, BOOP, AIP, or
NSIP. These usually represent a sampling error as a result of
an inadequate lung biopsy or a sample taken from a lesion that
has only end-stage histopathological features. It is these cases
that are referred to as “nonclassifiable” chronic interstitial
pneumonia. It is important that the surgical biopsy include
some areas of what appears to be “normal” lung to the surgeon, in order to exclude active lesions of other interstitial
lung diseases.
TREATMENT OF IPF
IPF progresses in a relentless and often insidious manner that
may be difficult to detect using parameters such as symptomatology, chest radiographic findings, or spirometry alone. Spontaneous remissions do not occur. In earlier clinical studies, the
clinical course of IPF was quite variable, with a mean survival
ranging from 4 to 6 yr after the time of diagnosis. However,
more recent clinical series of better defined cases of IPF have
identified a much shorter survival, with mean survival among
these studies ranging from 2 to 4 yr (5yr survival range, 30 to
50%) (11,103,163, 166,191).
Rationale for Treatment
The treatment of IPF has been based on the concept that inflammation leads to injury and fibrosis (1). Initially, it is hypothesized that inflammatory and immune effector cells accumulate within the pulmonary parenchyma. As this alveolar
and interstitial reaction is perpetuated, alveolar wall, vascular,
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and airway damage ensues; reparative processes are inadequate or impaired; and fibrosis develops. Eventually, the lung
parenchyma is irreversibly deranged and gas exchange function impaired. When the ventilatory reserve is sufficiently diminished, symptoms of respiratory insufficiency become apparent. Although this conceptualization of the pathogenetic
process suggests numerous theoretical points of therapeutic
intervention, the practical treatment armentarium has been
largely restricted to antiinflammatory medications and, most
recently, lung transplantation.
Optimal therapy for IPF is contentious (192). To date, most
treatment strategies have been based on eliminating or suppressing the inflammatory component. No pharmacological
therapy has been proven unequivocally to alter or reverse the
inflammatory process of IPF. More importantly perhaps, little
information has appeared supportive of the theory that the fibrotic process can be reversed. All currently available therapeutic trials in IPF are severely limited by the lack of clear understanding of the natural history of IPF, the presence of
many different study designs; heterogeneous patient groups,
disputable diagnostic certainty; variable study duration; differences in medication formulation, dosage, route of administration, and duration of treatment; lack of placebo controls; nonquantitative or differing types of assessment criteria; and
variable intervals between evaluations.
Conventional Treatment Options
Treatment options include corticosteroids (12, 20, 153, 193195), immunosuppressive/cytotoxic agents (e.g., azathioprine,
cyclophosphamide) (12, 13, 158) and antifibrotic agents (e.g.,
colchicine or o-penicillamine) (12, 160, 161, 196) alone or in
combination.
Corticosteroids. Despite their ubiquitous use, no prospective, randomized, double-blind, placebo-controlled trial has
evaluated the efficacy of corticosteroids in the treatment of
IPF (155). In three trials comparing corticosteroids with no
treatment, none of the untreated patients with IPF improved
(12, 16, 197). Given the limitations of existing studies that are
based on defined quantitative assessment criteria, 10 to 30%
of patients with IPF improve when treated with corticosteroids whereas up to 40% respond on the basis of subjective or
undefined assessment criteria. Responses are usually partial
and transient. Cures (i.e., sustained, complete remissions) are
achieved in few patients. Even among responders, relapses or
progression of the disease after an initial response suggests the
need for prolonged treatment.
Historically, most investigators initiate therapy with highdose corticosteroids (40 to 100 mg daily of prednisone or prednisolone) for 2 to 4 mo, with a subsequent gradual taper. However, no studies have compared differing dosages or duration
of corticosteroid in appropriately matched or randomized patients. If responses are to occur with corticosteroids, improvement is usually noted within 3 mo. After 3 mo of corticosteroid
therapy, objective clinical parameters (e.g., dyspnea scores,
physiological studies, chest radiographs, HRCT) are required
to gauge response. Subjective improvement is not adequate to
gauge response, because of placebo effects or mood-enhancing effects of corticosteroids.
Common practice has been for maintenance corticosteroid
therapy to be reserved for patients exhibiting stabilization or
objective improvement. Corticosteroid-responsive patients are
maintained on prednisone chronically (sometimes indefinitely),
but in a gradually tapering dose. Relapses or deterioration
warrant escalation of the dose or addition of an immunosuppressive agent. The dose of corticosteroid and rate of
taper should be guided by clinical and physiological parame-
American Thoracic
Society
ters. Since it is unlikely that corticosteroids completely eradicate the disease, prolonged treatment for a minimum of 1 to 2 yr
(and sometimes indefinitely) is reasonable for patients exhibiting unequivocal responses to therapy. In this context, chronic
low-dose prednisone (15 to 20 mg every other day) may be adequate as maintenance therapy. High-dose intravenous “pulse”
methylprednisolone (1 to 2 g once weekly or biweekly) has
been used, but has no proven advantage over oral corticosteroids (198).
Cytotoxic treatment. Immunosuppressive or cytotoxic agents
(e.g., azathioprine or cyclophosphamide) are used among steroid nonresponders, patients experiencing serious adverse effects from corticosteroids, and patients at high risk for corticosteroid complications (e.g., age > 70 yr, poorly controlled
diabetes mellitus or hypertension, severe osteoporosis, or peptic ulcer disease). Favorable responses have been noted in a few
small treatment trials with cytotoxic agents (e.g., azathioprine
or cyclophosphamide) in 15 to 50% of cases (195199,200).
Azathioprine. Azathioprine has been used as therapy for
IPF, primarily in patients failing or experiencing adverse effects from corticosteroids. Anecdotal responses were noted in
uncontrolled studies (200). The combination of azathioprine
plus corticosteroids was associated with modest improvement
and enhanced survival in some patients (195).
Cyclophosphamide. No convincing data exist to show a superiority of cyclophosphamide over corticosteroids in treating
IPF. In addition, no studies have directly compared cyclophosphamide with other immunosuppressive or cytotoxic agents
(158). High-dose intravenous (“pulse”) cyclophosphamide administered every 2 to 4 wk (dose range, 500 to 1,800 mg) has
been tried in open trials of refractory IPF (159, 201). Results
are generally unimpressive. The poor response to pulse cyclophosphamide likely reflects late course disease when treatment was instituted, rather than an intrinsic failure of cyclophosphamide therapy. No studies have compared oral with
pulse cyclophosphamide for IPF. Toxicity associated with cyclophosphamide remains a major impediment to the routine
use of this agent for IPF.
Potential Alternative Treatments
conference on therapy for pulmonary fibrosis underscored the marginal benefit of existing therapies and suggested that major advances in survival awaited the development of novel therapies (202). Studies assessing novel therapeutic
strategies require a better understanding of the pathogenesis
of the disease. Possible future (and completely untested) therapeutic strategies include: agents that inhibit cytokines, proteases, oxidants, or fibroblast growth factors; antifibrotic agents;
dietary modifications; more efficient intrapulmonary delivery of
drugs via liposomes; diphosphonates; antioxidants; inhibitors
of leukocyte integrins; and gene therapy (202). The following
is a brief review of some of these potential novel treatments.
Cyclosporin A. Cyclosporin A has only rarely been used in
IPF. Anecdotal responses have been noted but sustained remissions have been rare and toxicity is high (203). There are
few data to support its use in IPF.
Methotrexate. Methotrexate has been successfully used as
therapy for diverse immune-mediated pulmonary disorders.
Published data evaluating methotrexate as therapy for IPF are
lacking. The potential for pulmonary toxicity has dampened
enthusiasm for using methotrexate to treat IPF.
Chlorambucil. Chlorambucil has been used by some investigators as a substitute for cyclophosphamide in the treatment
of patients with IPF. Chlorambucil may cause gastrointestinal
and bone marrow toxicity and may induce neoplasia (includA consensus
655
ing leukemias). Given its toxicity and the lack of data as therapy for IPF, chlorambucil cannot be considered for treatment
of IPF.
Agents that alter collagen synthesis or fibrosis. Since therapeutic results achieved with immunosuppressive or antiinflammatory agents have been disappointing, novel strategies employing antifibrotic agents have been advocated, but their
value is unproven. Future therapies aimed at preventing or inhibiting the fibroproliferative response will be crucial in reducing the impact of this problem on the health of individuals
afflicted with IPF.
Colchicine. Colchicine inhibits collagen formation and modulates the extracellular milieu in vitro and in animal models; it
also suppresses the release of alveolar macrophage-derived
growth factor and fibronectin by in vitro-cultured alveolar
macrophages from patients with sarcoidosis or IPF (196). Although substantive data affirming the efficacy of colchicine as
therapy for IPF are lacking, the efficacy appears similar to corticosteroids and the side effects attributed to colchicine are
rarely severe (160, 161, 204). Thus, oral colchicine, 0.6 mg
once or twice daily, may be considered as first line therapy or
for patients refractory to corticosteroids, either alone or in
combination with immunosuppressive/cytotoxic agents. Additional controlled trials are needed to determine the appropriate role for colchicine in the treatment of IPF.
o-Penicillamine. Anecdotal evidence of responses to o-penicillamine have been noted in idiopathic or connective tissue
disease-associated pulmonary fibrosis but controlled studies
have not been done (12, 193, 194,204,205). o-penicillamine is
toxic, and significant adverse effects (e.g., loss of taste, nausea,
vomiting, stomatitis, nephrotoxicity) complicate its use in up
to 50% of patients. In view of its toxicity, and the lack of data
affirming its efficacy, o-penicillamine has no proven value as
therapy for IPF.
Other antifibrotic agents. Other antifibrotic agents are being tested in the treatment of lung fibrosis and include interferon y (206) interferon l3, relaxin (increases procollagenase),
pirfenidone (207) halfuginone (inhibits collagen synthesis),
suramin (profibrotic cytokine inhibition), and prostaglandin
Ez (inhibits collagen production).
Other novel agents. Because epithelial injury in IPF may be
mediated by oxygen radicals (208) it has been suggested that
antioxidant strategies might prove beneficial (209-211). Possible strategies might include delivery of antioxidant enzymes to
the lung parenchyma or even promoting increased genetic expression of antioxidant enzymes (202). Glutathione (an effective scavenger of toxic oxidants that suppresses lung fibroblast
proliferation in response to mitogens), taurine (a natural free
amino acid), and niacin inhibit the development of experimental fibrosis (better than either agent alone) in an animal
model. High-dose N-acetylcysteine, as a glutathione precursor,
has been suggested as an adjunct to maintenance immunosuppression therapy in patients with IPF (212).
Another potential strategy would be to interfere with the
process of leukocyte retention in the lung (202). Leukocyte
adhesion molecules play an important role in this process. Antibodies to such adhesion molecules have been shown to prevent collagen deposition in an animal model of lung injury
(213). Agents that block the expression or function of adhesion molecules are rapidly becoming available and may some
day prove clinically useful.
Although there is still much to be learned regarding the
roles of various cytokines and growth factors in the complex
process of pulmonary fibrosis, it is clear that these agents are
critical (214). Inhibitors of specific fibrogenic cytokines or growth
factors may help to retard the fibrotic process (215-217).
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
656
STAGING AND PROGNOSIS
Features Associated with Rate of Disease Progression
Several studies have identified features of IPF that are associated with an increased risk of more rapid disease progression
(142,146,218-221). Unfortunately, it appears that many of the
reported cases of IPF are in patients who present late in the
course of their disease (218). This point is particularly important since many of the features of IPF that have been found to
be associated with disease progression may only be relevant to
the late or terminal phase of this disease process. Moreover,
these findings suggest that efforts should be made to identify
patients with IPF earlier in the course of their disease, when it
is more likely that the clinical course may be altered by treatment.
Clinical deterioration is most frequently the result of disease progression; however, disease-associated complications
and adverse effects of therapy are also important complications to be considered. Respiratory failure is the most frequent cause of death, accounting for approximately 40% of
the deaths of patients with IPF. Other causes of death in patients with IPF include heart failure, ischemic heart disease,
infection, and pulmonary emboli (20). Bronchogenic carcinoma has been identified with increased frequency (10 to 15%
of patients) in advanced idiopathic pulmonary fibrosis. The
prognosis for patients with idiopathic pulmonary fibrosis and
lung cancer is poor.
Indicators of longer survival among patients with IPF include the following (12, 15,21, 156, 157,222,223):
Younger age (< 50 yr)
Female sex,
Shorter symptomatic period (s 1 yr) with less dyspnea,
relatively preserved lung function
Presence of ground glass and reticular opacities on
HRCT
Increased proportion of lymphocytes (20 to 25%) in BAL
fluid
A beneficial response or stable disease 3 to 6 mo after
initial corticosteroid therapy
A history of “current” cigarette smoking at the time of
diagnosis has been associated with improved survivalThis finding remains unexplained
The degree of dyspnea and need for treatment with immunosuppressive agents (proxy measures of the extent and severity of disease) were found to be independently associated with
progressive declines in both lung volumes and gas exchange
(218). Excess neutrophils (> 5%) (12) and/or eosinophils
(> 5%) (146,218,226) in the BAL fluid have been associated
with a higher likelihood of disease progression and a failure to
respond to immunosuppression. The extent of “fibrosis” on
HRCT scan has been shown to be an important predictor of
poorer survival (103). Risk stratification among patients with
IPF appears to be feasible and could provide the basis for a
clinical staging system.
Monitoring the Clinical Course of IPF
Currently, there is no standard approach to stage IPF clinically or pathologically (225). Although IPF is a progressive
form of interstitial lung disease, the extent and rate of progression vary markedly from one patient to the next. Thus, it is often difficult to determine if treatment is producing the desired
effect. Objective, validated parameters to assess disease activity and response to therapy have varied among studies. Sadly,
only a minority of patients with IPF respond to therapy. Subjective improvement occurs frequently (up to 70% of treated
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2000
patients) and should not be the lone factor in determining
whether to continue treatment. Objective improvement in physiologic abnormalities occurs in 20-30% of treated patients.
Changes in pulmonary functional parameters used to identify
“responders” (or “nonresponders”) have not been uniform.
Increases of only 10 to 15% from pretreatment baseline in
even single parameters of pulmonary function (e.g., VC,
DL~~) have been deemed favorable responses in some studies.
Radiographic improvement (especially on chest radiograph)
in patients with IPF has not been clearly documented and is
considered quite uncommon. Lack of change or “stabilization”
is considered by some investigators to represent a response
among patients previously exhibiting a downhill course. This
assessment of “response” may exaggerate the true impact of
therapy in ameliorating the course of the disease, particularly
when brief time periods (e.g., 3 to 6 mo) are analyzed. It is
common during the management of an individual patient with
IPF that some parameters used to assess the clinical course
may improve while others show declines or no change.
Given this, a system to assess the stage of disease activity
and the rate of progression is essential. A clinical, radiographic, and physiologic (CRP) scoring system that included
seven clinical variables (dyspnea, chest radiograph, spirometry, lung volume, diffusion capacity, resting alveolar-arterial
O2 difference, and exercise O2 saturation) was shown to correlate with the degree of fibrosis and the cellular histopathological component of the open lung biopsy from patients with IPF
(14). These findings suggested that a defined scoring system
might be best in staging the extent of IPF and helpful in monitoring the clinical course. Although these results are encouraging, further internal and external validity testing is needed
to develop a reliable staging system in IPF.
Repeated measurements of the following parameters are
believed to be useful in assessing the clinical course of IPF:
Assessment of dyspnea, using an established clinical
scale for rating the impact of dyspnea on activities. (Also,
it might also be useful to serially follow measures of
“quality of life,” using established instruments, but this
requires additional study [226])
Physiologic testing (227)
l Lung volumes
l DLCO
l Resting arterial blood gases (e.g., AaPo,)
l Cardiopulmonary exercise testing with measurement
of gas exchange
HRCT lung scans
RECOMMENDATIONS FOR TREATMENT
To date we lack sufficient clinical evidence that any treatment
improves survival or the quality of life for patients with IPF.
However, the potential for a positive outcome has encouraged
clinicians to treat these patients. Given the poor prognosis for
patient with IPF, many experts have recommended that treatment be initiated in all patients with IPF who do not have contraindications to therapy. The committee believes that therapy
is not indicated for all patients. Importantly, given the limited
success of current treatments, the potential benefits of any
treatment protocol for an individual patient with IPF may be
outweighed by increased risk for treatment-related complications (e.g., age > 70 yr, extreme obesity, concomitant major
illness such as cardiac disease, diabetes mellitus, or osteoporosis, severe impairment in pulmonary function, endstage honeycomb lung on radiographic evaluation).
The exact time that therapy should be started is unknown.
The committee believes that response rates may be higher
657
American Thoracic Society
when treatment is initiated early in the course of the disease,
before irreversible fibrosis has developed. Failures in some
cases appear to reflect delays in initiating treatment. Therefore, the committee recommends that if therapy will be offered to a patient, it should be started at the first identification
of clinical or physiological evidence of impairment or documentation of decline in lung function.
Until adequate studies are conducted that define the best
treatment for patients with IPF, this committee suggests the
following combined therapy (corticosteroid and either azathioprine or cyclophosphamide) for those patients who have been
given adequate information regarding the merits and pitfalls
of treatment and who possess features consistent with a more
likely favorable outcome (see above):
l
l
Corticosteroid therapy (prednisone or equivalent) at a
dose of 0.5 mg/kg (lean body weight [LBW]) per day
orally for 4 wk, 0.25 mg/kg (LBW) per day for 8 wk, and
then tapered to 0.125 mg/kg (ideal body weight [IBW])
daily or 0.25 mg/kg (LBW) every other day as initial
therapy for IPF. (Lean body weight is the ideal weight
expected for a patient of this age, sex, and height)
Azathioprine at 2-3 mg/kg lean body weight (LBW) per
day to a maximum dose of 150 mg/d orally. Dosing should
begin at 25-50 mg/d and increase gradually, by 25-mg
increments, every 7 to 14 d until the maximum dose is
reached
or
A decrease in symptoms, specifically an increase in the
level of exertion required before the patient must stop
because of breathlessness or a decline in the frequency or
severity of cough
Reduction of parenchymal abnormalities on chest radiograph or HRCT scan
Physiologic improvement defined by two or more of the
following:
l 2 10% increase in TLC or VC (or at least > 200-ml
change)
l 2 15% increase in single-breath DL~~ (or at least 2 3
ml/min/mm Hg)
saturation
l An improvement or normalization of O2
(2 4 percentage point increase in the measured saturation) or Paoz (a 4-mm Hg increase from the previous measurement) achieved during a formal cardiopulmonary exercise test
A stable (and presumed favorable) response to therapy is
defined by two or more of the following, documented on two
consecutive visits over a 3- to 6-mo period:
l
l
Cyclophosphamide at 2 mg/kg LBW per day to a maxi-
mum dose of 150 mg/d orally. Dosing should begin at 2550 mgld and increase gradually, by 25-mg increments, every 7 to 14 d until the maximum dose is reached
Length of Therapy
A discernible objective response to therapy may not be evident until the patient has received 2 3 mo of therapy. Consequently, in the absence of complications or adverse effects of
the medications, combined therapy should be continued for at
least 6 mo. At that time, repeat studies should be performed to
determine the response to therapy (see below, M ONITORING
FOR
The committee recommends that a combination of factors be
used to assess the response to treatment and clinical course of
IPF:
A favorable (or improved) response to therapy is defined by
two or more of the following, documented on two consecutive
visits over a 3- to 6-mo period:
A DVERSE E FFECTS OF T REATMENT).
Six months after onset of therapy:
l
l
If the patient is found to be worse the therapy should be
stopped or changed (e.g., continue prednisone at present
dose and switch to different cytotoxic agent or consider
an alternative therapy or lung transplantation)
If the patient is found to be improved or stable the combined therapy should be continued, using the same doses
of the medication(s)
Twelve months after onset of therapy:
l
l
If the patient is found to be worse the therapy should be
stopped or changed (e.g., consider an alternative therapy
or lung transplantation)
If the patient is found to be improved or stable the combined therapy should be continued, using the same doses
of the medication(s)
More than 18 mo after onset of therapy. At this point, therapy should be individualized on the basis of the clinical response and tolerance of the patient to the therapy. The committee recommends that the therapy be continued indefinitely
only in individuals with objective evidence of continued improvement or stabilization.
l
l
10% change in TLC or VC, or < 200-ml change
< 15% change in DL~~, or < 3 ml/min/mm Hg
No change in O2 saturation (< 4% increase) or Pao, (< 4mm Hg increase) achieved during a formal cardiopulmonary exercise test
A failure to respond to therapy (e.g., after 6 mo of treatment) is defined as:
l
l
l
An increase in symptoms, especially dyspnea or cough
An increase in opacities on chest radiograph or HRCT
scan, especially the development of honeycombing or signs
of pulmonary hypertension
Evidence of deterioration in lung function in two or
more of the following:
l 1 10% decrease in TLC or VC ( or s 200-ml change)
l 3 15% decrease in single-breath DL~~ (or at least
2 3-ml/min/mm Hg change)
l Worsening (greater fall) of O2 saturation (2 4 percentage point decrease in the measured saturation) or
rise in the AaPoz at rest or during a formal cardiopulmonary exercise test (2 4 mm Hg increase from the
previous measurement)
Monitoring for Adverse Effects of Treatment
Before starting therapy, patients should be informed about
the potential risk and side effects of corticosteroid and cytotoxic therapy. Corticosteroid therapy is usually tolerated by
patients; however, side effects are common and potentially
disabling. Some patients develop side effects of corticosteroids
more readily than others at equivalent doses. Efforts should
be made to reduce or prevent side effects if possible. Peptic
ulcer disease, posterior capsular cataracts, increased intraocular pressure, hypertension, endocrine and metabolic alterations (deposition and redistribution of fatty tissue with truncal
obesity, moon facies, menstrual irregularities, impotence, hyperglycemia, hypokalemia, metabolic alkalosis, and secondary adrenal insufficiency) may occur. Potential musculoskeletal
complications are osteoporosis, vertebral compression frac-
658
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
tures, aseptic necrosis of femoral and humeral heads, and myopathy. The latter may impair diaphragmatic and intercostal
muscle strength and endurance, and these changes may complicate the assessment of therapeutic efficacy. Psychologic effects including euphoria, depression, or psychosis may also be
encountered, especially in elderly patients (228). Methods to
reduce the risk of steroid-induced osteoporosis should be instituted, especially in postmenopausal women, since even
short-term therapy (3 to 6 mo) may cause reductions in bone
mass. Unfortunately, the success of such regimens remains to
be determined.
Azathioprine is less toxic than cyclophosphamide, as azathioprine does not induce bladder injury and has less oncogenie potential. The maximal dose of azathioprine or cyclophosphamide need not be adjusted according to the lowering
of the white blood cell count. However, if the white blood cell
count decreases to c 4,OOO/mm’ and the platelet counts fall
below 100,000/mm” then the dose of azathioprine or cyclophosphamide should be stopped or lowered immediately by
50% of the current dose until these hematologic abnormalities
recover. Recovery of the white blood cell (WBC) and platelet
counts should be assessed weekly. If the counts do not recover, the medication should be completely discontinued until
these abnormalities improve. On occasion the white blood cell
count remains > 7,OOO/mm” despite increases in the azathioprine or cyclophosphamide dose. In those instances, the dose
should not exceed 150 mg/d. Patients taking azathioprine
should also undergo monthly measurements of hepatocellular
injury, and the dose of the medication should be reduced or
stopped if abnormalities greater than three times the normal
level are found. Forced diuresis, 2 8 glasses (8 oz. each) of water daily, and monthly monitoring of the urine for red blood
cells or other abnormality is recommended in an attempt to
prevent clinically significant hemorrhagic cystitis in patients
treated with cyclophosphamide.
Corticosteroid therapy may suppress the immune response
to skin tests; therefore, when possible, tuberculin skin testing
is advisable before the initiation of steroid therapy. The routine use of trimethoprim/sulfamethoxazole (one single-strength
tablet three times weekly) as prophylaxis against Pneumocystis carinii or isoniazid as prophylaxis against Mycobacterium
tuberculosis in patients receiving immunosuppressive therapy
may be considered. Preventive therapy is recommended for
persons with a positive tuberculin skin test or those at risk
(e.g., individuals living in endemic areas), and in particular
those patients taking > 15 mg of prednisone (or equivalent)
daily for more than 3 wk. However, limited data exist to identify the risk of these infectious complications in this setting.
Other Management Issues
Patients with IPF should be encouraged to enroll in a pulmonary physical rehabilitation program. These patients are usually so dyspneic with exertion that they discontinue any program of routine exercise. This discontinuation of exercise
should not be encouraged since the primary goal is to restore
patients to the highest possible functional state. No data from
carefully defined studies of pulmonary rehabilitation in the
management of patients with IPF have been reported. However, the panel recommends that for motivated patients a
combination of exercise training, education, and psychosocial
support may help, not by improvements in lung function,
which are not likely to occur, but with improvement in exercise tolerance, together with decreased symptoms of breathlessness, improved quality of life, and less need for health care
services (229). Daily walks or the use of a stationary bicycle
are excellent routines. Severe hypoxemia (Paoz. less than 55
VOL 161
2000
mm Hg) at rest or during exercise should certainly be managed by supplemental OZ. Supplemental O2 during exercise
may markedly improve exercise-induced hypoxemia and improve exercise performance (228,229). Higher flow rates than
that frequently used in chronic obstructive pulmonary disease
may be required.
Severe paroxysms of cough may be among the most distressing features of IPF. A variety of antitussive agents have
been used, but controlled studies assessing efficacy have not
been done. Rib fractures secondary to protracted episodes of
cough may occur in elderly individuals with severe osteoporosis. Oral codeine or other antitussives may be helpful in some
patients and should be tried in patients with cough refractory
to over-the-counter medications. Pulmonary hypertension may
complicate IPF in the late phases of the disease (20). However, administration of vasodilators to reduce pulmonary arterial pressure has not been shown to be beneficial and may
cause serious adverse effects (including systemic hypotension). Opioids have been used to reduce dyspnea in patients
with severe chronic lung disease, but data affirming the efficacy of this practice are lacking. Low-dose (2.5 to 5 mg) nebulized morphine failed to improve dyspnea or exercise tolerance in patients with interstitial lung disease (232).
Lung Transplantation
Transplantation should be considered for those patients who
experience progressive physiologic deterioration despite optimal medical management and who meet the established criteria (233,234). Single lung transplantation is currently the preferred surgical operation. Unless specific contraindications
exist, patients with severe functional impairment, oxygen dependency, and a deteriorating course should be listed for lung
transplantation. Relative contraindications to lung transplantation include unstable or inadequate psychosocial profile/stability, or significant extrapulmonary disorders (e.g., liver, renal, or cardiac dysfunction) that may negatively influence
survival. Many centers limit lung transplantation candidates to
those < 60 yr of age.
Owing to limited donor availability, early listing is important, as the waiting time for procuring a suitable donor organ
may exceed 2 yr. Unfortunately, patients with rapidly progressive or severe IPF may die while awaiting transplantation. After successful transplantation, arterial oxygen tension is frequently sufficiently improved to alleviate the requirement for
supplemental oxygen, lung volumes and DL~~ are increased,
and pulmonary hypertension and right ventricular dysfunction
are reversed.
The decision to list patients for transplantation is sobering,
as 5-yr survival after transplantation approximates 50 to 60%.
Graft failure, infection, and heart failure are the most common causes of early mortality whereas bronchiolitis obliterans, infection, and malignancy are responsible for most late
mortality.
LIMITATIONS AND FUTURE GOALS
There are limited data on the full spectrum of cases of IPF. In
fact, most of the reported studies suggest that patients with
IPF generally present late in the course of their disease. This
point is particularly important since many of the features of
IPF that have been found to be associated with disease progression may be relevant only to the terminal phase of this disease process. Moreover, these findings indicate that efforts
should be made to identify patients with IPF earlier in the
course of their disease.
American Thoracic Society
Case definition varies between studies; therefore, comparison of study populations is compromised. Selection bias exists,
with the least selection bias occurring in population-based
studies, although these studies are difficult to do and few are
available for patients with IPF. As noted, there has been only
one population-based study to date in the United States. In
addition, many epidemiological studies rely on vital statistic
data for information. These data have been shown repeatedly
to be inaccurate and incomplete for the disease IPF. Cooperative interaction among investigators is necessary for population-based studies to claim the greatest degree of information
and to learn more about the epidemiology of this disease. Obtaining historical information about occupational, environmental, and family history is critical to focus on the risk factors
for the development of IPF. Improvement in tracking the disease on an international level needs to occur. Further studies
of genetic predisposition to IPF are needed, with a challenge
as to which gene(s) or marker(s) of susceptibility to focus investigations.
Prospective, controlled studies to critically evaluate the diverse immunosuppressive or antifibrotic agents available to
the therapeutic armamentarium of IPF are required. Despite
widespread clinical use of azathioprine and cyclophosphamide
for patients with IPF who have failed corticosteroids, data directly comparing these agents are lacking. Further, many
studies have employed these agents combined with corticosteroids. Despite anecdotal successes, the superiority of these alternative agents over corticosteroids has not convincingly
been established. Owing to the rarity of IPF, and the heterogeneity of its clinical expression, prospective trials assessing
specific agents will be fraught with difficulty. In addition to requiring a large number of clinical centers from which to draw
an adequate number of subjects, it will be critical to match patients for severity. duration of illness, and activity of disease at
entry, using objective, well-defined markers. The use of diagnostic tests such as HRCT scans or BAL to separate early inflammatory disease from late fibrosis may discriminate patient
populations likely to benefit from aggressive antiinflammatory or antifibrotic therapy.
Given the lack of definitive data on therapeutic efficacy in
the treatment of IPF, the committee strongly recommends the
establishment of a multicenter, international consortium to allow the recruitment of sufficient numbers of subjects needed
to determine the optimal treatment strategy for IPF. Mapel
and colleagues estimated that if we assume a 5-yr survival of
SO%, it would take at least 712 patients to detect a 20% improvement in survival (accrual time, 1 yr; follow-up time, 5 yr;
type I error rate, 0.05; power, 0.80) (155). Given current estimates of the incidence of IPF, this would require a population
base of approximately 7.7 million to capture, enroll, and randomize every incident case (155). Also, the studies should be
randomized placebo-controlled trials. The use of a placebo
group is attractive from a scientific viewpoint and is strongly
encouraged but may discourage patients or physicians from
participating in controlled trials largely because of the need to
“do something” for this progressive, debilitating disease (155).
However, a randomized placebo-controlled study would provide the most valuable data because it would overcome the
bias and confounding effects of previous observational
studies, allow identification of the natural history of IPF, and
allow the identification of risk of complications of the therapy
(155).
Acknowledgment: Rosalind F. Dudden (MLS, Health Sciences Librarian)
and Barbara Criss (Information Specialist at the National Jewish Medical
and Research Center) are thanked for performing the literature search. B. 1.
Burnett, Mary DeJesus, and Nancy Esajian are thanked for their assistance.
659
The authors thank Drs. Thomas Colby, David Hansell, Masanori Kitaichi, and
William Travis for their critical review of the manuscript.
This statement was prepared by an ad-hoc committee of the Assembly
on Clinical Problems. Members of the committee are:
T ALMADGE E. KI N G, JR ., M.D., C h a i r
ULRICH~OSTABEL, M.D.
JEAN-FRANCOK CORDIER, M.D.
G UILLERMO A. DOPICO, M.D.
R OLAND M. DIJ BOIS, M.D.
D AVID L Y N C H, M.B.
J OSEPH P. LY N C H, III, M.D.
J E F F R E Y M Y E R S, M.D.
R A L P H P A N O S , M.D.
G A N E S H R A G H U , M.D.
D A V I D S C H W A R T Z , M.D.
C ECILIA M. SM I T H, D.O.
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